title: Expansion of memory-type CD8+ T cells correlates with the failure of early immunosuppression withdrawal after cadaver liver transplantation using high-dose ATG induction and rapamycin.
abstract: BACKGROUND
  We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin.
  
  
  METHODS
  LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells.
  
  
  RESULTS
  Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (Vβ/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells.
  
  
  CONCLUSIONS
  High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-γ and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.
authors.affiliation: Department of Abdominal Surgery and Transplantation, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. vincent.donckier@erasme.ulb.ac.be
authors.forename: Vincent
authors.initials: V
authors.lastname: Donckier
authors.forename: Ligia
authors.initials: L
authors.lastname: Craciun
authors.forename: Patrick
authors.initials: P
authors.lastname: Miqueu
authors.forename: Roberto Ivan
authors.initials: RI
authors.lastname: Troisi
authors.forename: Valerio
authors.initials: V
authors.lastname: Lucidi
authors.forename: Xavier
authors.initials: X
authors.lastname: Rogiers
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boon
authors.forename: Delphine
authors.initials: D
authors.lastname: Degré
authors.forename: Alexis
authors.initials: A
authors.lastname: Buggenhout
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
authors.forename: Thierry
authors.initials: T
authors.lastname: Gustot
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sainz-Barriga
authors.forename: Nadine
authors.initials: N
authors.lastname: Bourgeois
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.forename: Mohammed
authors.initials: M
authors.lastname: Amrani
authors.forename: Myriam
authors.initials: M
authors.lastname: Remmelink
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lemmers
authors.forename: Dave L
authors.initials: DL
authors.lastname: Roelen
authors.forename: Frans H
authors.initials: FH
authors.lastname: Claas
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Alain
authors.initials: A
authors.lastname: Le Moine
authors.forename: Bernard
authors.initials: B
authors.lastname: de Hemptinne
authors.forename: Michel
authors.initials: M
authors.lastname: Goldman
mesh_terms: D000328:Adult; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002102:Cadaver; D003587:Cytomegalovirus / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D015851:Interleukin-7 / Q000097:blood; D007518:Isoantibodies / Q000097:blood; D016031:Liver Transplantation; D008212:Lymphocyte Depletion; D020123:Sirolimus / Q000008:administration & dosage*
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D015851:Interleukin-7; D007518:Isoantibodies; D020123:Sirolimus